Technology of Solid Dosage Forms &Disperse Systems

Facilitated by/

Mekaiel Amiel Mekaiel M.Sc. Pharmaceutical Technology

National University

Suppositories

Definition:

• Suppositories are solid (some

times semi solid) dosage forms

suitably shaped for insertion

into natural body orifices

(rectum, vagina and Urethra).

• They can be used for local or

systemic action.

REASONS FOR SUPPOS.:

1. If the patient is not able to use the drug orally: in case of pediatric or geriatric patients, GIT

disturbance, post operative, or unconscious patients. 2. If the drug is unsuitable for oral use: cause GIT irritation, unstable in GIT fluids, or

undergo excessive first pass metabolism. Also, drugs with an unacceptable taste can be administered rectally without this inconvenience to the patient. The formulation into suppositories of certain drugs that are candidates for abuse, as in suicide, has also been considered.

Drawbacks:

1. Slow or incomplete absorption,

2. Development of proctitis,

3. High cost of production, and

4. Relatively short shelf-life.

5. Depending on tradition, there are strong

feelings of aversion in certain countries

to rectal administration of drugs.

USES:

1. Local use:

used for local pain or itching, the commonly used

drugs are:

astringents, anti septic, local anaesthetics,

vasoconstrictors, anti inflammatory, soothing &

protective agents, and laxatives.

2. Systemic use:

all orally used drugs can be used , the commonly

used drugs are:

Anti asthmatics, anti rheumatics, and analgesics

Absorption of drugs from the

rectum

• Blood supply, especially venous

drainage, is important for the

understanding of drug absorption. The

lower and middle haemorrhoidal veins

drain directly into the general

circulation; the upper one drains into

the portal vein, which flows to the liver.

Continue Absorption

• This means that drug molecules can

enter the general circulation directly or

by passing through the strongly

metabolizing liver.

• Thus the bioavailability may be less

than 100%. Compared to the small

intestine this situation is still more

favorable.

CLASSIFICTION:

• Depending on the character of the base

(vehicle) they can be classified into:

1. Dissolved in the rectal fluids,

2. Melt in the mucus layer.

FORMULATION OF SUPPOSITORIES

SUPPOSITORIES BASES-

IDEAL PROPERTIES OF SUPPOSITRIES BASES-

1. Bases should exist in solid form at room

temperature.

2. It should not irritate and produce inflamed sensation

in body cavity.

3. It should be stable during storage condition , No

change in colour, shape , odour.

4. It should retain hardness and shape during

manufacturing and handling.

IDEAL PROPERTIES OF SUPPOSITRY BASES

5. It should not reacts with drugs and additives.

6. It should have good emulsifying and wetting

property.

7. It should have acid value less than 0.2 or zero.

8. It should have iodine value less than 7.

9. It should have saponification no. range between200-

245.

Water soluble and Water-Miscible

Bases

• Used mainly as laxtives or in vaginal

therapy,

• They are:

a) Glycerin- gelatin or soap bases,

b) Macrogoles (mixture of PEGs),

(1)WATER DISPERSIBLE BASES-

(1) HYDROPHILIC BASES

These are the mixture of non ionic surfactants which

are chemically related to polyethylene glycol.

These are used alone or in combination with other

type of bases.

Cellulose derivatives like methylcellulose,

sod.carboxymethyl cellulose are also comes under

this class.

Advantages

They are suitable for both water soluble and oil

soluble drugs.

They do not support the growth of microbes in the

preparation.

They can be stored at elevated temperature.

Disadvantages-

This types of bases interact with few drugs and alter

the bioavailability of these drugs.

EXAMPLES

Polyoxyethylene sorbitan fatty acid ester(TWEENS)

Polyoxyethelene stearates(MYRIS)

Sorbitan fatty acid esters(SPANS)

Combination of Tween 61(60%) and Tween 60(40%)

Combination of Tween 61 (85%) and glyceryl

monostearate (15%)

(2) WATER SOLUBLE BASES (1) GLYCERO-GELATIN-

This occurs as a gels

It is a mixture of gelatin, glycerol, and water.

According to BP the composition of the bases –

GELATIN- 14% w/w

GLYCEROL– 70% w/w

WATER

To gets a stiff mass , the quantity of gelatin should be

increased to 32.5% and reduce the glycerol to 40%.

Glycero-gelatin bases have a physiological effect

when they dissolve in the mucous secretions of the

rectum (osmosis).

This is useful if a laxative effect is required but

otherwise is undesirable.

PREPARATION OF GLYCERO-GELATINE

BASES

GLYCERO

L WATER GELATINE

GLYCERO-GELATINE BASES

ADVANTAGES

Suppository prepared by glycero-gelatin bases are

strong and translucent unlike cocoa butter

suppositories.

This base disperse slowly in the body cavity fluids and

provides prolonged release and action of drugs.

DISADVANTAGES-

It absorbs moisture and promotes microbial growth , so

for this reason preservatives are used .

b) Macrogols

• Are polyethylene glycols which are blended

together to produce suppository bases

which vary in melting point, dissolution rates

and physical characteristics.

• They are brittle, and have no physiological

effect (laxative effect) and are not prone to

microbial contamination.

• They are hygroscopic and irritation of the

rectal mucosa can occur.

POLY ETHYLENE GLYCOL

(POLYGLYCOL)

It is also called as PASTONALS (GERMANY).

CARBOWAXES(U.S)

They are long chain polymers of ethylene

oxide.

They occur in liquid and solids.

Liquids have mol.weight about 200-600.

Solid have mol.weight about more than 1000.

They are also called as macrogols.

They are the mixture of two or more grades of

macrogols used as suppository bases.

EXAMPLES

PEG 4000- 33 parts

PEG 6000- 47 parts

PURIFIED WATER- 20 parts

FOR HARD SUPPOSITORY

PEG 1000- 75 parts

PEG 4000- 25 parts

FOR SOFT SUPPOSITORY

PEG 1000- 96 parts

PEG 4000- 4 parts

ADVANTAGES

1. This base is thermostable.

2. It does not get degraded or hydrolyzed.

3. It does not support microbial growth.

4. It dose not move out from body cavity after introducing.

5. It has good water absorbing capacity.

6. It is chemically stable.

DISADVANTAGES

1. It is susceptible to rancidification, so it should be

stored in dry place away from light.

2. It melt easily in warm weather, so it should be stored

in cool place in warm season.

3. Large quantities of water can not be incorporated into

the bases. So emulsifier such as tween 61 (6-10%) are

useful to increase the absorption of water.

4. The physical characteristics of the bases change from

batch to batch.

5. Some times leakage may be occur after introducing in

body cavity.

LIPOPHILIC BASES

(a) Naturally occurring eg COCOA BUTTER

It is natural triglyceride.

Among all fatty acid about 40% are unsaturated fatty

acid .

It can exist in more than one crystalline form or

exhibits polymorphism.

At room temperature ,it is yellowish-white with a

paints chocolate like odour.

It consists of a mixture of ester of oleic acid,palmatic

acid,stearic acid and other fatty acid with glycerol.

ADVANTAGES

1. It has a melting point range of 30-36oC and therefore is solid at normal room temperature.

2. It liquifies readily on warming and sets rapidly on cooling.

3. It has emollient effect which is useful to relieve inflammation.

4. It shows good release of water soluble drugs.

5. It does not cause irritation in mucous membrane.

DISADVANTAGES

1. It is susceptible to rancidification ,so it should be

stored in dry place away from light.

2. It gives soft suppository when formulated along with

chloral hydrate , phenol, volatile oil, which have lower

melting point.

3. It is chemically unstable it suffers from polymorphism,

4. It required extra lubricant during poring in holder.

5. Some times leakage may be occur.

6. high cost.

B) Semi synthetic synthetic: • They are prepared by hydrogenating suitable

vegetable oils. • The viscosity of the synthetic fats, when melted, is

lower than that of thiobroma oil, and there is a risk of the active ingredient regimenting during the preparation process.

• These bases become brittle if cooled too rapidly, so should not be refrigerated during the preparation period.

• Most manufacturers market a series of grades of synthetic fatty bases, e.g. Witepsol

• They are (termed deps solidus) they are mixed triglycerides with c12- c18 acids.

ANTI OXIDANTS

It protects the drugs and bases from geting degraded

due to oxidation.

These are commonly used in all types of

suppositories.

EXAMPLES-

Ethyl or propyl gallate

Ascorbic acid

Butylated hydroxy anisole (BHA)

Butylated hydroxy toluene (BHT)

Hydroquinone

Tocopherol

EMULSIFYING AGENTS

These increase the water absorbing capacity of fatty

bases.

EXAMPLES

Poly sorbates (TWEEN 61)

Wool alcohol

Wool fats

HARDENING AGENTS

These are involved in those formulation where the

melting point of the bases decrease by the drugs.

These are the agents which are used to bring the

melting point to normal.

EXAMPLES

Beeswax

Macrogols at high molecular weight.

PRESERVATIVES

These are the agents which are used in prevent the

microbial growth in suppository which contains water

soluble bases.

EXAMPLES

Chorocresol

Methyl paraben

Propyl paraben

THICKENING AGENTS

These are the agents which are used to increases the

viscosity of molten bases and prevent sedimentation

of suspended material in solid bases.

EXAMPLES

Aluminium monostearate

Colloidal silica

Magnisium stearate

Stearyl alcohol

PLASTICIZERS

These are the agent which are used to improved

flexibility of suppositories.

It is also used to make the suppositories less brittle.

EXAMPLES

Castor oils

Glycerine

Glycol

Tween 80

Tween 85

Formulation of supposotories

• They are formulated in many shapes and sizes weighing 1-4 g.

• The drug content varies from 0.1%- 40% of its weight,

• It consists of drug, vehicle, and some times additives.

• The bases are of two types:

1. Fatty bases,

2. Water soluble bases.

Manufacture:

• They can be manufactured by:

1. Molding method,

2. Compression.

Molding method • Suitable for all types of suppositories

bases:

The process includes:

1. melting or dissolving the base,

2. incorporation of the medicament into the

melt base,

3. pouring the melt into molds,

4. allowing the melt to cool and congeal and

5. finally removal of the formed

suppositories from the molds.

(B) COMPRESSION MOLDING

CONSTRUCTION- The compression machine

consists of a cylinder, piston , molds, and a metallic

stop plate at the bottom.

WORKING- When placed the mass in cylinder and

apply the pressure .

Then mass fulfill in mold move and remove the

suppositories and keep them in cool placed.

After cooling release them from compression

machine and packed .

PROCEDURE

DRUG+ADDITIVES FINE POWDER

MIXED WITH BASES

LUBRICANTS APPLY IN MOLDS

PLACED THE MASSES IN CYLINDER

APPLY PRESSURE

RELEASE SUPPOSITORY

COOLED PACKED STORED

ADVANTAGE-

It is suitable for thermolabile drugs because in this

method no heat is required.

Rate of production is more.

DISADVANTAGE-

The main disadvantage is air entrapment occurs

during production so oxidation takes place in

suppository.

• STORAGE CONDITION

It is stored at 10-15 0c

Used air tight container

The suppositories with cocoa butter stored at < 30 0c.

The suppositories with glycero-gelatin stored at < 35 0c.

EVALUATION OF SUPPOSITORIES

1. Test of appearance(size , shape)

2. Test of physical strength

3. Test of dissolution rate

4. Test of melting range

5. Test of softening time

6. Test of uniformity of drug content

STABILITY PROBLEMS OF

SUPPOSITORIES

BLOOMING-

During storage , cocoa butter suppositories

sometimes show deposition of white powder on the

surface.

This result in suppositories of disagreeable

appearance.

HARDENING-

During storage , the suppositories made of fatty bases

become hard.

It occurs due to crystallization of bases.

This also effect the melting and rate of absorption of

drugs.

Q.C of Suppositories: 1. content uniformity,

2. weight uniformity ,

3. dissolution test

4. drug release,

5. breaking test (Fragility and brittleness of

the product, the weight at which

suppository collapse),

6. organolibtic properties:

done by cutting 2 suppositories longitudinally and inspect the internal and external surfaces of the suppositories visually to observe their appearance (entrapped air bubbles, powder distribution, smoothness of the outer surface……etc)

7. Liquefaction or softening time test:

(time elapsed for a rod to go through a suppository at different temperatures),

8. melting range test:

done using tablet disintegration tester adjusted at 37oC by introduction of 3 suppositories in the tester keeping the assembly in the immersed position (No need for up and down movement of the assembly),

recording the time when the suppositories start to melt and time the melting is complete.

Calculate melting point range (in minutes) as the difference between the recorded times.

BP stated that three suppositories should melt or disintegrate within 30min except glycerinated gelatin based ones where 1 hr is regarded as upper limit for them,

THANKS